The cytokine, leukemia inhibitory factor (LIF), has been shown to be a potential therapeutic molecule for neurological disorders, including stroke. While LIF has been shown to activate cellular survival pathways, exact mechanisms have yet to be elucidated. Our laboratory has shown that LIF protects cultured oligodendrocytes (OLs) from oxygen glucose deprivation (OGD). One of its mechanisms is by increasing the expression of antioxidant enzymes, metallothinein-3 (Mt3) and peroxiredoxin-4 (Prdx4), to reduce extracellular oxidative stress. The proposed experiments will elucidate the LIF signaling mechanisms leading to the increased expression of the Mt3 and Prdx4 to reduce oxidative stress. Our hypothesis is that LIF protects oligodendrocytes exposed to ischemic conditions via antioxidant signaling. This proposal will utilize an in vitro model of ischemia to define the signaling pathway responsible for the protective and antioxidant effects of LIF. Moreover, we will expand on these results to determine in vivo whether delayed i.v. administration of LIF protects OLs in the rat brain from focal cerebral ischemia through increased antioxidant activity. Lastly we will test this delayed administration for its efficacy to enhance long-term behavioral recovery. This proposal will provide the data for additional animal studies to examine LIF as a potential therapeutic to widen the treatment window for stroke. PUBLIC HEALTH RELEVANCE: Stroke is a major health problem in the USA with only one FDA-approved treatment, which has a limited therapeutic window. We have found that leukemia inhibitory factor (LIF) protects neural cells from ischemia through increasing the expression of anti-oxidant enzymes thus reducing oxidative stress. The experiments within this proposal will define this novel LIF-induced signal pathway that enhances neural cell survival both in cultured cells and in a rat model of stroke. Moreover, the administration of LIF at clinical relevant time points will be evaluated for its ability to increase behavioral recovery after stroke. Thus, if successful, this would be a novel therapeutic approach to stroke treatment that can be administered non-invasively.